The hormone-sensitive adenylyl cyclase system is the target of bacterial toxins that alter its activity by catalyzing the ADP- ribosylation of critical guanine nucleotide-binding (G) regulatory proteins that couple hormone receptors to the cyclase catalytic unit. An inhibitory G protein (Gi) is ADP-ribosylated by pertussis toxin, an etiological agent in whooping cough, whereas a stimulatory G protein (Gs) is ADP-ribosylated by cholera toxin (CT) and E. coli heat-labile enterotoxins (LT), etiological agents in cholera and "travelers' diarrhea", respectively. The ADP- ribosyltransferase activities of CT and the LTs are enhanced by - 19 kDa soluble and membrane guanine nucleotide-binding proteins, known as ADP-ribosylation factors (ARFs); in the case of the LTs, it appears that although two of them, LT-IIa and LT-IIb, diverge in amino acid sequence from LT-I and CT, the sites involved in ARF- stimulated ADP-ribosylation have been conserved. CT and LT catalyze reactions similar to those of ADP-ribosyltransferases endogenous to animal cells. These transferases ADP-ribosylate arginine residues in proteins as well as free arginine. In animal tissues, ADP-ribosylarginine hydrolases exist that cleave the ADP- ribose-arginine linkage, regenerating the arginine residues; these enzymes are active as monomers of 39 kDa; it appears that the ADP- ribosylarginine hydrolase and the ADP-ribosyltransferase could catalyze opposing arms of an ADP-ribosylation cycle analogous to the kinases and phosphatases in protein phosphorylation cyclase. In addition, the ADP-ribosylarginine hydrolases, by reversing the toxin-catalyzed reactions, may promote recovery from disease.